The present invention relates to compounds, or their pharmaceutical compositions, for systemic use and non, to be used in the antimicrobial therapy.
It is known that the wide use of antimicrobial agents in the infection treatment has caused the development of strains resistant to these drugs, for example the case of antiviral, antifungal and antibacterial agents can be mentioned.
This resistance generally arises when microorganisms develop growth and reproduction mechanisms on which the antimicrobial therapy is ineffective, or when the microorganisms produce enzymes which neutralize the drug. The resistant microbial strain is then able to multiply, causing the illness prolongation and worsening, with possible diffusion of the infection in the communities. This fact, as known, can determine notable consequences at a social-economic and sanitary level.
A method to solve this problem is to increase the dosage of the antimicrobial drugs. In this way there is the drawback of an increased incidence of side effects both local and systemic. Besides, cases of microbial superinfection deriving from the antimicrobial agent itself due to the inbalance between pathogen and non pathogen microbial flora often occur. It is well known that antimicrobial agents must act on the pathogen agents which are responsible of the unhealthy process and leave unaltered the non pathogen microbes useful for the organism.
A widely followed approach for solving the problem of the microbial resistance, and/or of the diffusion of pharmaco-resistant strains, has been to introduce in therapy new molecules to be used as antimicrobial agents. The results so far obtained are not satisfactory.
The need was therefore felt to have available drugs able not only to be active on the microorganism but also to prevent and/or reduce the microbial resistance and therefore to allow a complete and effective antimicrobial therapy, said drugs being effective at the conventional minimum dosages to avoid the side toxic effects. Among the latter skin rash and the effects on the stomach, liver and kidney can for example be mentioned.
It has been surprisingly and unexpectedly found by the Applicant that it is possible to solve the above technical problem by using compounds which have shown to be able to effectively interact with microbes and to prevent or reduce the microbial resistance.
An object of the present invention is the use of nitrate salts of antimicrobial agents, or their pharmaceutical compositions, for the preparation of medicaments usable in the treatment of infectious diseases. Preferably the invention relates to the use of nitrate salts of antiviral, antifungal and antibacterial agents, or their pharmaceutical compositions; the antimicrobial agents usable for preparing the nitrate salts of the present invention must satisfy the following test: in the culture of specific pathogen microbes responsible for the single pathologies, the antimicrobial agent is inoculated at a concentration such as to result effective as antimicrobial agent and such as not to produce cytotoxicity in mammalian cells.
See for example the test of the dilution in vitro on medium reported in the Examples for the antibacterial agents.
More specifically the present invention relates to the use of nitrate salts of compounds, or their pharmaceutical compositions, for preparing medicaments usable in the treatment of infectious diseases as antimicrobial agents, said compounds preferably being selected from the following classes:
class I) 
wherein:
R1=H, Cl or dimethylamino,
R2=H, OH, or free valence,
R3=H, CH3, when R2 is free valence with the doublet of the Cxe2x80x94R3 bond it forms a double bond and R3 is methylene,
R4=H, OH,
R5=H, CH2OH, or one of the following substituents: 
class II) 
wherein:
X and Y, different the one from the other, are C or N,
R6=ciclopropyl, C2H5, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoroethyl,
R7=H, amino, CH3,
R8=H or F, when Y=N, R8 is free valence and it is the free doublet on the nitrogen atom,
R9=H, CH3 or one of the following substituents: 
wherein M=H, CH3, C2H5, OH, 
wherein T1 is H, OH 
R8 and R9 taken together form the bivalent radical having formula: xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 (IIP),
R10=H, Cl, F, when X=N, R10 is free valence and it is the free doublet on the nitrogen atom, R6 and R10 taken together form the following bivalent radicals: 
when X in the formula (II)=N, R10 is free valence and it forms a double bond with the carbon atom adjacent to the nitrogen;
class IIIa): 
wherein:
Z=S, C,
R11=H, pivaloyloxymethylene of formula (IIIaF) wherein T2 is the tert-butyl group,
R12=Cl, CH3, acetyloxymethylene of formula (IIIaF) wherein T2 is CH3, 2-propenyl or one of the following substituents: 
R13=amino, OH, or the substituent (IIIaD): 
R14 is phenyl, 4-hydroxyphenyl, or the radical (IIIaE);
class IIIb) 
wherein:
X=CH, N.
Y=C, N,
R15=COOH, COOxe2x88x92, (CH3)3CCOOCH2OCOxe2x80x94 or (CH3)2CHOCOOCH(CH3)OCOxe2x80x94,
R16=H, CH3, C2H5, xe2x80x94CHxe2x95x90CH2, NH2COOCH2xe2x80x94, CH3COOCH2xe2x80x94, or one of the following substituents: 
when R15 is carboxylated anion R16 is a radical selected from the following: (IIIbL), (IIIbM) or (IIIbN)
R17=OH, OCH3, C2CH5, xe2x80x94OCH2COOH, xe2x80x94CH2COOH;
class IIIc) 
wherein:
R18 is one of the following substituents: 
R19=H, CH3COOCH2xe2x80x94, or one of the following groups: 
class IVa: 
wherein:
R20 is one of the following substituents: 
R21=H, the radical (IIIaF) with T2=tert-butyl, CH(CH3)OCOOC2H5 or one of the following substituents:
xe2x80x94CH2CH2N(CH2CH3)2.HIxe2x80x83xe2x80x83(IVaR), 
class IVb) 
wherein:
R22=H, CH3,
R23 is selected from the following groups:
xe2x80x94CH2CH2NHCHxe2x95x90NHxe2x80x83xe2x80x83(IVbD), 
class IVc) 
wherein:
R33, R34, R36, equal to or different from each other, are H, CH3;
R35=H, xe2x80x94CH2OCONH2,
class V) 
wherein
R24=H, Br, OCH3, CH3OCH2CH2Oxe2x80x94;
class VI) 
wherein:
R25 is one of the following substituents: 
class VII) 
wherein
R26=H, or one of the following substituents: benzoyl, acetyl, 3-methyl-2-butenoyl, carbamoyl, aminothioxo NH2C(S)xe2x80x94 2-pyridinyl, pyrazinyl, 2-pyrimidinyl, 2-thiazolyl, salicyl-4-yl, 6-chloro-pyridazine-3-yl, 1-ethyl-1,2-dihydro-2-oxo-pyrimidin-4-yl, 5,6-dimethoxy-pyrimidin-4-yl, 2,6-dimethoxy-Pyrimidin-4-yl, 4-methyl-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 6-methoxy-2-methyl-pyrimidin-4-yl, 5-methyl-pyrimidin-2-yl, 2,6-dimethyl pyrimidin-4-yl, 3-methoxy-pyrazine-2-yl, 6-methoxy-pyridazin-3-yl, 4,6-diethyl-1,3,5-triazin-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-methoxy-1,2,5-thiadiazol-3-yl, 4-methyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4,5-dimethyl-oxazol-2-yl, 3,4-dimethyl-isooxazol-5-yl, 4,5-dimethyl-2-oxazolylaminoiminomethyl, 5-methyl-isooxazol-3-yl, 1-phenyl-1H-pyrazol-5-yl, 4-methylamino sulphonylphenyl, 4-amino-sulphonylphenyl, 3,4-dimethylbenzoyl, 4-isopropoxy benzoyl;
class VIII) 
wherein:
R27=H, 4,6-dimethyl-pyrimidin-2-yl;
R28=2,4-diamino-6-carboxyphenyl, 2,4-diaminophenyl, 3-car-boxy-4-hydroxyphenyl;
class IX) 
wherein:
R29=H, OH,
R30=COOH, phenoxycarbonyl, 4-(amino)phenylsulphinyl, hydra-zinecarbonyl;
class X) 
wherein:
R31=amino, NH2xe2x80x94CH2xe2x80x94, benzylamino,
R32=amino, 4-(hydroxyethylamino)phenyl, xe2x80x94Nxe2x95x90C(NH2)2, 4-(amino)phenyl, 4-(aminomethyl) phenyl, 4-(carboxymethyl amino)phenyl, 4-(carboxypropionyl amino)phenyl, 2-amino-thiazol-5-yl;
class XI) 
wherein:
M=O, S,
R52=H, C2H5, C3H7,
R53=amino, xe2x80x94NHNH2, or one of the following substituents: 
class XII) 
wherein:
R37=Cl, OH;
class XIIIa) 
wherein:
R38=H, acetyl, COC2H5 (propionyl),
R39=H, propionyl, COC3H7 (butyryl), COCH2CH(CH3)2 (isovaleryl),
R40=H, propionyl,
R41=H, or: 
class XIIIb) 
wherein:
R47=H, CH3,
W=CO (carbonyl), xe2x80x94N(CH3)CH2xe2x80x94,
R48=H, or R48 together with W forms the bivalent radical: 
class XIVa) 
wherein:
R42=OH, amino,
R43=H, (R)-4-amino-2-hydroxybutyryl, (S)-4-amino-2-hydroxybutyryl,
R44=H, OH,
R45=H, OH;
class XIVb) 
wherein:
R46=xe2x80x94CH2OH; xe2x80x94CHO
Class XIVc) 
wherein:
R49=CH3, C4H9;
class XIVd) 
wherein:
R50=H, C2H5,
R51=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl: 
Class XIVe) 
wherein:
R60=OH, amino,
R61=H or one of the following substituents: 
Class XV) 
wherein
R54=CH3, cyclopentyl;
Class XVIa) 
wherein:
Xb=N, C,
R55=H, amino,
R56=H, OH, amino,
R57 xc3xa9 xcex2-D-ribofuranosyl or 4-acetoxy-3-(acetoxymethyl)1-bu-tyl;
Class XVIb) 
wherein:
R58=H, amino,
R59=CH2OCH2CH2OH, CH2OCH(CH2OH)CH2OH, CH2OCH2CH2OCOCH(NH2)CH(CH3)2, xcex2-D-(2,3-dideoxy)ribofuranosyl;
Class XVII): the following compounds:
O-2-amino-2-deoxy-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-[3-deoxy-3-(methylamino)-xcex1-D-xylopyranosyl-(1xe2x86x926)]-2-deoxy-D-streptamine (Gentamycin A), 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazol (Metronidazole), (S)-2-amino-5-[(aminoiminomethyl)amino]pentanoic acid (Arginine), (+)-2,2xe2x80x2-(ethylendiimino)di-1-butanol (Ethambutol), 1-aminoadamantane (Amantadine), 2xe2x80x2,3xe2x80x2-dideoxy-cytidine (zalcitabine), Pyrazinamide, Morfazinamide, Acetylsulfamethoxypyrazine, Clofazimine, Cycloserine, Streptonicizid, Deoxydihydrostreptomycin, Mikamycin, Rosaramicin, Carbomycin, Alexidine, Ambazone, Cloxiquin, Negamycin, Nitroxoline, Porfiromycin, Taurolidine, Tibezonium iodide, Apramycin, Teicoplanin, Vancomycin, Thiabendazole, Mebendazole, Albendazole, Acranil, Anisomycin, Dimetridazole, Diminazene, Aceturate, Eflornithine, Halofuginone, Homidium, Hydroxystilbamidine, Imidocarb, Ipronidazole, Lauroguadine, Nimorazole, Oxophenarsine, Pentamidine, Phenamidine, Propamidine, Puromycin, Pyrimethamine, Quinacrine, Quinapyramine, Quintine, Secnidazole, Stilbamidine, Tinidazole.
In class I:
when R1=H, R2=OH, R3=CH3, R4=H, R5=(IA), the compound is known as Apicycline,
when R1=Cl, R2=OH, R3=CH3, R4=H, R5=H, the compound is known as Chlortetracycline,
when R1=Cl, R2=OH, R3=CH3, R4=H, R5=CH2OH, the compound is known as Clomocycline,
when R1=Cl, R2=OH, R3=H, R4=H, R5=H, the compound is known as Demeclocycline,
when R1=H, R2=H, R3=CH3, R4=OH, R5=H, the compound is known as Doxycycline,
when R1=H, R2=OH, R3=CH3, R4=H, R5=(IB), the compound is known as Guamecycline,
when R1=H, R2=OH, R3=CH3, R4=H, R5=(ID), the compound is known as Lymecycline,
when R1=Cl, R2=free valence and with the doublet of the Cxe2x80x94R3 bond it forms a double bond, and R3 is methylene, R4=OH, R5=H, the compound is known as Meclocycline,
when R1=H, R2=free valence and with the doublet of the Cxe2x80x94R3 bond it forms a double bond, and R3 is methylene, R4=OH, R5=H, the compound is known as Methacycline,
when R1=dimethylamino, R2=H, R3=H, R4=H, R5=H, the compound is known as Minocycline,
when R1=H, R2=OH, R3=H, R4=OH, R5=H, the compound is known as Oxytetracycline,
when R1=H, R2=OH, R3=CH3, R4=H, R5=(IC), the compound is known as Pipacycline,
when R1=H, R2=OH, R3=CH3, R4=H, R5=H, the compound is known as Tetracycline;
when R1=H, R2=H, R3=H, R4=H, R5=H, the compound is known as Sancycline.
In class II:
when R6=cyclopropyl, R7=H, R8=F, R9=(IIA) with M=H, R10=H, X=Y=C, the compound is known as Ciprofloxacin,
when R6=cyclopropyl, R7=H, R8=F, R9=(IIF), R10=Cl, X=Y=C, the compound is known as Clinaloxacin,
when R6=4-fluorophenyl, R7=H, R9=F, R9=(IID), R10=H, X=Y=C, the compound is known as Difloxacin,
when R6=C2H5, R7=H, R8=F, R9=(IIA) with M=H, R10=free valence, X=N, Y=C, the compound is known as Enoxacin,
when R6=cyclopropyl, R7=H, R8=F, R9=(IIA) with M=C2H5, R10=H, X=Y=C, the compound is known as Enrofloxacin,
when R6=fluoroethyl, R7=H, R8=F, R9=(IIA) with M=CH3, R10=F, X=Y=C, the compound is known as Fleroxacin,
when R6 with R10 forms the bivalent radical (IIM), R7=H, R8=F, R9=H, X=Y=C, the compound is known as Flumequine,
when R6=cyclopropyl, R7=CH3, R8=F, R9=(IIB), R10=H, X=Y=C, the compound is known as Grepafloxacin,
when R6=ethyl, R7=H, R8=F, R9=(IIB), R10=F, X=Y=C, the compound is known as Lomefloxacin,
when R6 with R10 forms the bivalent radical (IIM), R7=H, R8=F, R9=(IIE) with T1=OH, X=Y=C, the compound is known as Nadifloxacin,
when R6=C2H5, R7=H, R8=H, R9=CH3, R10=free valence, X=N, Y=C, the compound is known as Nalidixic acid,
when R6=C2H5, R7=H, R8=F, R9=(IIA) with M=H, R10=H, X=Y=C, the compound is known as Norfloxacin,
when R6 with R10 forms the bivalent radical (IIN), R7=H, R8=F, R9=(IIA) with M=CH3, X=Y=C, the compound is known as Ofloxacin,
when R6=C2H5, R7=H, R8 and R9 form the bivalent radical (IIP), R10=H, X=Y=C, the compound is known as Oxolinic acid,
when R6 with R10 forms the bivalent radical (IIO), R7=H, R8=F, R9=(IIH), X=Y=C, the compound is known as Pazufloxacin,
when R6=ethyl, R7=H, F, R9=(IIA) with M=CH3, R10=H, X=Y=C, the compound is known as Pefloxacin,
when R6=C2H5, R7=H, R8=free valence, R9=(IIA) with M=H, R10=free valence, X=Y=N, the compound is known as Pipeimidic acid,
when R6=C2H5, R7=H, R8=free valence, R9=(IIE) with T1=H, R10=fre valence, X=Y=N, the compound is known as Piromidic acid,
when R6 with R10 forms the bivalent radical (IIQ), R7=H, R8=F, R9=(IIA) with M=CH3, X=Y=C, the compound is known as Rufloxacin,
when R6=cyclopropyl, R7=amino, R8=F, R9=(IIC), R10=F, X=Y=C, the compound is known as Sparfloxacin,
when R6=2,4-difluorophenyl, R7=H, R8=F, R9=(IIF), R10=free valence, X=N, Y=C, the compound is known as Tosufloxacin,
when R6=2,4-difluorophenyl, R7=H, R8=F, R9=(IIG), R10=free valence, X=N, Y=C, the compound is known as Trovafloxacin,
when R6=cyclopropyl, R7=H, R8=F, R9=(IID), R10=H, X=Y=C, the compound is known as Danofloxacin,
when R6=4-fluorophenyl, R7=H, R8=F, R9=(IIA) with M=H, R10=H, X=Y=C, the compound is known as Sarafloxacin.
In class IIIa:
when R11=H, R12=Cl, R13=amino, R14=phenyl, Z=S, the compound is known as Cefaclor,
when R11=H, R12=CH3, R13=amino, R14=4-hydroxyphenyl, Z=S, the compound is known as Cefafroxil,
when R11=H, R12=(IIIaB), R13=amino, R14=4-hydroxyphenyl, Z=S, the compound is known as Cefatrizine,
when R11=H, R12=(IIIaC), R13=(IIIaD), R14=4-hydroxyphenyl, Z=S, the compound is known as Cefpiramide,
when R11=H, R12=2-propenyl, R13=amino, R14=4-hydroxyphenyl, Z=S, the compound is known as Cefprozil,
when R11=H, R12=CH3, R13=amino, R14=(IIIaE), Z=S, the compound is known as Cefroxadine,
when R11=H, R12=CH3, R13=amino, R14=phenyl, Z=S, the compound is known as Cephalexin,
when R11=H, R12=CH3, R13=(IIIaF) with T2=CH3, R14=phenyl, Z=S, the compound is known as Cephaloglycin,
when R11=H, R12=CH3, R13=amino, R14=(IIIaE), Z=S, the compound is known as Cephadrine,
when R11=H, R12=Cl, R13=amino, R14=phenyl, Z=C, the compound is known as Loracarbef,
when R11=(IIIaF) with T2=tert-butyl, R12=CH3, R13=amino, R14=phenyl, Z=S, the compound is known as Pivcefalexin,
when R11=H, R12=(IIIaC), R13=OH, R14=phenyl, Z=S, the compound is known as Cefamandole.
In class IIIb:
when R15=(CH3)3CCOOCH2OCOxe2x80x94, R16=NH2COOCH2xe2x80x94, R17=C2H5, X=CH, Y=C, the compound is known as Cefcapene Pivoxil,
when R15=COOxe2x88x92, P16=(IIIbL), R17=methoxyl, X=Y=N, the compound is known as Cefclidin,
when R15=COOH, R16=xe2x80x94CH=CH2, R17=OH, X=N, Y=C, the compound is known as Cefdinir,
when R15=COOH, R16=(IIIbA), R17=OCH3, X=N, Y=C, the compound is known as Cefditoren,
when R15=COOxe2x88x92, R16=(IIIbM), R17=OCH3, X=N, Y=C, the compound is known as Cefepime,
when R15=COOH, R16=CH3, R17=OCH3, X=N, Y=C, the compound is known as Cefetamet,
when R15=COOH, R16=xe2x80x94CH=CH2, R17=xe2x80x94OCH2OCOOH, X=N, Y=C, the compound is known as Cefixime,
when R15=COOH, R16=(IIIbC), R17=OCH3, X=N, Y=C, the compound is known as Cefmenoxime,
when R15=COOxe2x88x92, R16=(IIIbN), R17=OCH, X=Y=N, the compound is known as Cefozopran,
when R15=(CH3)2CHOCOOCH(CH3)OCOxe2x80x94, R16=C2H5, R17=OCH3, X=N, Y=C, the compound is known as Cefpodoxime Proxetil,
when R15=COOH, R16=(IIIbD), R17=OCH3, X=N, Y=C, the compound is known as Cefteram,
when R15=COOH, R16=H, R17=xe2x80x94CH2COOH, X=CH, Y=C, the compound is known as Ceftibuten,
when R15=COOH, R16=(IIIBH), R17=OCH3, X=N, Y=C, the compound is known as Ceftriaxone,
when R15=COOH, R16=(IIIbE), R17=OCH3, X=N, Y=C, the compound is known as Cefuzonam,
when R15=COOH, R16=(IIIbF), R17=OCH3, X=N, Y=C, the compound is known as Cefodizime,
when R15=COOH, R16=CH3COOCH2xe2x80x94, R17=OCH3, X=N, Y=C, the compound is known as Cefotaxime,
when R15=COOH, R16=(IIIbG), R17=OCH3, X=N, Y=C, the compound is known as Ceftiofur.
In class IIIc:
when R18=(IIIcD), R19=(IIIcH), the compound is known as Cefotiam,
when R18=(IIIcE), R19=H, the compound is known as Ceftizoxime,
when R18=(IIIcF), R19=(IIIcN), the compound is known as Cefazolin,
when R18=(IIIcG), R19=(IIIcM), the compound is known as Ceforanide,
when R18=(IIIcA), R19=(IIIcL), the compound is known as Cefminox,
when R18=(IIIcB), R19=CH3COOCH2xe2x80x94, the compound is known as Cephalosporin C.
In Class IVa:
when R20=(IVaF) and R21=H, the compound is known as Amdinocillin,
when R20=(IVaF) and R21=(IIIaF) with T2=tert-butyl, the compound is known as Amdinocillin Pivoxil,
when R20=(IVaA) and R21=H, the compound is known as Amoxicillin,
when R20=(IVaB) and R21=H, the compound is known as Ampicillin,
when R20=(IVaM) and R21=H, the compound is known as Apalcillin,
when R20=(IVaG) and R21=H, the compound is known as Aspoxicillin,
when R20=(IVaB) and R21=xe2x80x94CH(CH3)OCOOC2H5, the compound ia known as Bacampicillin,
when R20=(IVaE) and R21=H, the compound is known as Cyclacillin,
when R20=(IVaC) and R21=H, the compound is known as Epicillin,
when R20=(IVaC) and R21=H, the compound is known as Hetacillin,
when R20=(IVaC) and R21=(IVaS), the compound is known as Lenampicillin,
when R20=(IVa) and R21=H, the compound is known as Mezlocillin,
when R20=(IVaD) and R21=(IVaR), the compound is known as Penethamate Hydroiodide,
when R20=(IVaP) and R21=H, the compound is known as Penicillin N,
when R20=(IVaB) and R21=(IIIaF) with T2=tert-butyl, the compound is known as Pivampicillin,
when R20=(IVaN) and R21=H, the compound is known as Quinacillin,
when R20=(IVaB) and R21=(IVaU), the compound is known as Sultamicillin,
when R20=(IVaB) and R21=(IVaT), the compound is known as Talampicillin.
In class IVb:
when R22=CH3, R23=(IVbA), the compound is known as Meropenem,
when R22=H, R23=(IVbC), the compound is known as Panipenem,
when R22=H, R23=(IVbD), the compound is known as Imipenem.
In class IVc:
when R23=CH3, R34=CH3, R35=H, R36=CH3, the compound is known as Aztreonam,
when R33=H, R34=H, R35=xe2x80x94CH2OCONH2, R36=H, the compound is known as Carumonam.
In class V:
when R24=Br, the compound is known as Brodimoprim,
when R24=OCH3, the compound is known as Trimethoprim,
when R24=CH3OCH2CH2Oxe2x80x94, the compound is known as Tetroxoprim.
In class VI:
when R25=(VID) the compound is known as Furaltadone,
when R25=(VIC) the compound is known as Furazolium chloride,
when R25=(VIE) the compound is known as Nifurfoline,
when R25=(VIA) the compound is known as Nifurpirinol,
when R25=(VIB) the compound is known as Nifurprazine.
In class VII:
when R26=H, the compound is known as Sulfanilamide,
when R26=benzoyl, the compound is known as Sulfabenzamide,
when R26=acetyl, the compound is known as Sulfacetamide,
when R26=3-methyl-2-butenoyl, the compound is known as Sulfadicramide,
when R26=carbamoyl, the compound is known as Sulfanilylurea,
when R26=NH2C(S)xe2x80x94, the compound is known as Sulfathiourea,
when R26=2-pyridinyl, the compound is known as Sulfapyridine,
when R26=pyrazinyl, the compound is known as Sulfapyrazine,
when R26=2-pyrimidinyl, the compound is known as Sulfadiazine,
when R26=2-thiazolyl, the compound is known as Sulfathiazole,
when R26=salicyl-4-yl, the compound is known as 4-sulphanilamido salicylic acid,
when R26=6-chloro-pyridazinyl-3-yl, the compound is known as Sulfachlorpyridazine,
when R26=1-ethyl-1,2-dihydro-2-oxo-pyrimidin-4-yl, the compound is known as Sulfacytine,
when R26=5,6-dimethoxy-pyrimidin-4-yl, the compound is known as Sulfadoxine,
when R26=2,6-dimethoxy-pyrimidin-4-yl, the compound is known as Sulfadimethoxine,
when R26=4-methyl-pyrimidin-2-yl, the compound is known as Sulfamerazine,
when R26=5-methoxy-pyrimidin-2-yl, the compound is known as Sulfameter,
when R26=4,6-dimethyl-pyrimidin-2-yl, the compound is known as Sulfamethazine
when R26=6-methoxy-2-methyl-pyrimidin-4-yl, the compound is known as Sulfamethomidine,
when R26=5-methyl-pyrimidin-2-yl, the compound is known as Sulfaperine,
when R26=2,6-dimethylpyrimidin-4-yl, the compound is known as Sulfisomidine,
when R26=3-methoxy-pyrazin-2-yl, the compound is known as Sulfalene,
when R26=6-methoxy-pyridazin-3-yl, the compound is known as Sulfamethoxypyridazine,
when R26=4,6-diethyl-1,3,5-triazin-2-yl, the compound is known as Sulfasymazine,
when R26=5-ethyl-1,3,4-thiadiazol-2-yl, the compound is known as Sulfaethidole,
when R26=5-methyl-1,3,4-thiadiazol-2-yl, the compound is known as Sulfamethizole,
when R26=4-methoxy-1,2,5-thiadiazol-3-yl, the compound is known as Sulfametrole,
when R26=4-methyl-thiazol-2-yl, the compound is known as Sulfamethylthiazole,
when R26=3-methyl-isothiazol-5-yl, the compound is known as Sulfasomizole,
when R26=4,5-dimethyl-oxazol-2-yl, the compound is known as Sulfamoxole,
when R26=3,4-dimethy-isoxazol-5-yl, the compound is known as Sulfisoxazole,
when R26=4,5-dimethyl-2-oxazolylaminoiminomethyl, the compound is known as Sulfaguanol,
when R26=5-methyl-isoxazol-3-yl, the compound is known as Sulfamethoxazole,
when R26=1-phenyl-1H-pyrazol-5-yl, the compound is known as Sulfaphenazole,
when R26=4-methylamino sulphonylphenyl, the compound is known as 4xe2x80x2-(methylsulfamoyl)sulfanilanilide,
when R26=4-aminosulphonylphenyl, the compound is known as Nxe2x88x924 sulfanilylsulfanilamide,
when R26=3,4-dimethylbenzoyl, the compound is known as N-sulfanyl-3,4-xylamide,
when R26=4-isopropoxybenzoyl, the compound is known as Sulfaproxyline.
In class VIII:
when R27=H, R28=2,4-diamino-6-carboxyphenyl, the compound is known as Sulfachrysoidine,
when R27=H, R28=2,4-diaminophenyl, the compound is known as Sulfamidochrysoidine,
when R27=4,6-dimethyl-pyrimidin-2-yl, R28=3-carboxy-4-hydroxyphenyl, the compound is known as Salazo sulfadimidine.
In class IX:
when R29=OH, R30=COOH, the compound is known as p-Aminosalicylic acid,
when R29=OH, R30=hydrazinecarbonyl, the compound is known as p-Aminosalicylhydrazide,
when R29=OH, R30=phenoxycarbonyl, the compound is known as Phenylaminosalicylate,
when R29=H, R30=4-(amino)phenylsulphinyl, the compound is known as 4,4xe2x80x2-Sulphinyldianiline.
In class X:
when R31=amino, R32=4-(hydroxyethylamino)phenyl, the compound is known as 2-p-Sulfanilylanilino ethanol,
when R31=amino, R32=xe2x80x94N=C(NH2)2, the compound is known as Sulfaguanidine,
when R31=NH2CH2xe2x80x94, R32=amino, the compound is known as Mafenide,
when R31=benzylamino, R32=amino, the compound is known as Benzylsulfamide,
when R31=amino, R32=4-(carboxymethylamino)phenyl, the compound is known as Acediasulfone,
when R31=amino, R32=4-(amino)phenyl, the compound is known as Dapsone,
when R31=amino, R32=4-(carboxypropionylamino)phenyl, the compound is known as Succisulfone,
when R31=amino, R32=4-(aminomethyl)phenyl, the compound is known as p-Sulfanilylbenzylamine,
when R31=amino, R32=2-amino-thiazol-5-yl, the compound is known as Thiazolsulfone.
In class XI:
when R52=C2H5, R53=amino, M=S, the compound is known as Ethionamide,
when R52=H, R53=xe2x80x94NHNH2, M=O, the compound is known as Isoniazid,
when R52=C3H7, R53=amino, M=S, the compound is known as Protionamide,
when R52=H, R53=(XIA), M=O, the compound is known as Sulfoniazide,
when R52=H, R53=(XIB), M=O, the compound is known as Verazide,
when R52=H, R53=(XIC), M=O, the compound is known as Opiniazide,
when R52=H, R53=(XID), M=O, the compound is known as Salinazid,
when R52=H, R53=(XIE), M=O, the compound is known as Furonazide,
when R52=H, R53=(XIF), M=O, the compound is known as Glyconiazide.
In class XII:
when R37=Cl, the compound is known as Clindamycin,
when R37=OH, the compound is known as Lincomycin.
In class XIIIa:
when R38=acetyl, R39=isovaleryl, R40=H, R41=H, the compound is known as Josamycin,
when R38=propionyl, R39=propionyl, R40=H, R41=H, the compound is known as Midecamycin A1,
when R38=H, R39=butyryl, R40=propionyl, R41=H, the compound is known as Rokictamycin,
when R38=H, R39=H, R40=H, R41=(XIIIaB), the compound is known as Spiramycin I,
when R38=acetyl, R39=H, R40=H, R41=(XIIIaB), the compound is known as Spiramycin II,
when R38=propionyl, R39=H, R40=H, R41=(XIIIaB), the compound is known as Spiramycin III,
when R38=H, R39=isovaleryl, R40=H, R41=H, the compound is known as Leucomycin.
In class XIIIb:
when R47=H, R48=H, W=xe2x80x94N(CH3)CH2xe2x80x94, the compound is known as Azithromycin,
when R47=CH3, R48=H, W=carbonyl, the compound is known as Clarithromycin,
when R47=H, R48=H, W=carbonyl, the compound is known as Erythromycin,
when R47=H, R48 and W for together (XIIIbA), the compound is known as Dirithromycin.
In class XIVa:
when R42=OH, R43=(S)-4-amino-2-hydroxybutyryl, R44=OH, R45=OH, the compound is known as Amikacin,
when R42=amino, R43=(R)-4-amino-2-hydroxy butyryl, R44=H, R45=H, the compound is known as Arbekacin,
when R42=amino, R43=H, R44=H, R45=H, the compound is known as Dibekacin,
when R42=amino, R43=H, R44=OH, R45=H, the compound is known as Tobramycin.
In class XIVb:
when R46=xe2x80x94CH2OH, the compound is known as Dihydrostreptomycin,
when R46=xe2x80x94CHO, the compound is known as Streptomycin.
In class XIVc:
when R49=CH3, the compound is known as Spectinomycin,
when R49=C4H9, the compound is known as Trospectomycin.
In class XIVd:
when R50H, R51=(XIVdA), the compound is known as Micronomicin,
when R50=C2H5, R51=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl, the compound is known as Netilmicin,
when R50=H, R51=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl, the compound is known as Sisomicin.
In class XIVe:
when R60=amino, R61=(XIVeA) the compound is known as Neomycin,
when R60=OH, R61=(XIVed) the compound is known as Paromycin,
when R60=amino, R61=H, the compound is known as Ribostamycin.
In class XV:
when R54=CH3, the compound is known as Rifampin,
when R54=cyclopentyl, the compound is known as Rifapentine.
In class XVIa:
when Xb=N, R55=H, R56=OH, R57=xcex2-D-ribofuranosyl, the compound is known as Inosine,
when Xb=N, R55=amino, R56=H, R57=4-acetoxy-3-(acetoxymethyl)1-butyl, the compound is known as Famcyclovir,
when Xb=C, R55=H, R56=amino, R57=xcex2-D-ribofuranosyl, the compound is known as Tubercidin.
In class XVIb:
when R58=H, R59=xcex2-D-(2,3-dideoxy)ribo furanosyl, the compound is known as Didanosine,
when R58=amino, R59=CH2OCH2CH2OH, the compound is known as Acyclovir,
when R58=amino, R59=CH2OCH2CH2OCOCH(NH2)CH(CH3)2, the compound is known as Valacyclovir,
when R58=amino, R59=CH2OCH(CH2OH)CH2OH, the compound is known as Gancyclovir.
The following compounds are preferred:
In class I:
when R1=H, R2=H, R3=CH3, R4=OH, R5=H, the compound is known as Doxycycline,
when R1=H, R2=OH, R3=H, R4=OH, R5=H, the compound is known as Oxytetracycline,
when R1=H, R2=OH, R3=CH3, R4=H, R5=H, the compound is known as Tetracycline.
In class II:
when R6=cyclopropyl, R7=H, R8=F, R9=(IIA) with M=H, R10=H, X=Y=C, the compound is known as Ciprofloxacin,
when R6=C2H5, R7=H, R8=H, R9=CH3, R10=free valence, X=N, Y=C, the compound is known as Nalidixic acid,
when R6=C2H5, R7=H, R8=F, R9=(IIA) with M=H, R10=H, X=Y=C, the compound is known as Norfloxacin,
when R6 with R10 form the bivalent radical (IIN), R7=H, R8=F, R9=(IIA) with M=CH3, X=Y=C, the compound is known as Ofloxacin.
In class IIIa:
when R11=H, R12=Cl, R13=amino, R14=phenyl, Z=S, the compound is known as Cefaclor,
when R11=H, R12=CH3, R13=amino, R14=phenyl, Z=S, the compound is known as Cephalexin,
when R11=H, R12=(IIIaC), R13=OH, R14=phenyl, Z=S, the compound is known as Cefamandole.
In class IIIb:
when R15=COOH, R16=ethenyl, R17=xe2x80x94OCH2OCOOH, X=N, Y=C, the compound is known as Cefixime,
when R15=(CH3)2CHOCOOCH(CH3)OCOxe2x80x94, R16=C2H5, R17=OCH3, X=N, Y=C, the compound is known as Cefpodoxime Proxetil,
when R15=COOH, R16=(IIIbF), R17=OCH1, X=N, Y=C, the compound is known as Cefodizime.
In class IIIc:
when R18=(IIIcF), R19=(IIIcN), the compound is known as Cefazolin.
In class IVa:
when R20=(IVaA) and R21=H, the compound is known as Amoxicillin,
when R20=(IVaB) and R21=H, the compound is known as Ampicillin,
when R20=(IVaM) and R21=H, the compound is known as Apalcillin.
In class IVb:
when R22=H, R23=(IVbD), the compound is known as Imipenem.
In class IVc:
when R33=CH3, R34=CH3, R35=H, R36=CH3, the compound is known as Aztreonam.
In class V:
when R24=OCH3, the compound is known as Trimethoprim.
In class VI:
when R25=(VIE) the compound is known as Nifurfoline.
In class VII:
when R26=5-methyl-isoxazol-3-yl, the compound is known as Sulfamethoxazole.
In class X:
when R31=amino, R32=4-(amino)phenyl, the compound is known as Dapsone.
In class XI:
when R52=C2H5, R53=amino, M=S, the compound is known as Ethionamide;
when R52=H, R53=xe2x80x94NHNH2, M=O, the compound is known as Isoniazid.
In class XIIIb:
when R47=H, R48=H, W=xe2x80x94N(CH3)CH2xe2x80x94, the compound is known as Azithromycin,
when R47=H, R48=H, W=carbonyl, the compound is known as Erythromycin,
when R47=CH3, R48=H, W=carbonyl, the compound is known as Clarithromycin.
In class XIVa:
when R42=OH, R43=(S)-4-amino-2-hydroxybutyryl, R44=OH, R45=OH, the compound is known as Amikacin,
when R42=amino, R43=H, R44=OH, R45=H, the compound is known as Tobramycin.
In class XIVb:
when R46=xe2x80x94CHO, the compound is known as Streptomycin.
In class XIVc:
when R49=CH3, the compound is known as Spectinomycin.
In class XIVd:
when R50=C2H5, R51=3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl, the compound is known as Netilmicin.
In class XIVe:
when R60=amino, R61=(XIVeA) the compound is known as Neomycin.
In class XV:
when R54=CH3, the compound is known as Rifampin.
In class XVIa:
when Xb=N, R55=H, R56=OH, R57=xcex2-D-ribofuranosyl, the compound is known as Inosine,
when Xb=N, R55=amino, R56=H, R57=4-acetoxy-3-(acetoxymethyl)1-butyl, the compound is known as Famcyclovir.
In class XVIb:
when R58=H, R59=xcex2-D-(2,3-dideoxy)ribo furanosyl, the compound is known as Didanosine,
when R58=amino, R59=CH2OCH2CH2OH, the compound is known as Acyclovir,
when R58=amino, R59=CH2OCH2CH2OCOCH(NH2)CH(CH3)2, the compound is known as Valacyclovir,
when R58=amino, R59=CH2OCH(CH2OH)CH2OH, the compound is known as Gancyclovir.
In class XVII:
O-2-amino-2-deoxy-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-[3-deoxy-3-(methylamino)-xcex1-D-xylopyranosyl-(1xe2x86x926)]-2-deoxy-D-streptamine (Gentamycin A), (S)-2-amino-5-[(aminoiminomethyl)amino]pentanoic acid (Arginine), (+)-2,2xe2x80x2-(ethylendiimino)di-1-butanol (Ethambutol), 1-amino adamantan (Amantadine), 2xe2x80x2,3xe2x80x2-dideoxy-cytidine (zalcitabine), Pyrazinamide, Morphazinamide, Teicoplanin, Vancomycin, Metronidazole
A further object of the invention are also the nitrate salts compounds of antimicrobial, preferably antiviral, antifungal and antibacterial agents, or their pharmaceutical compositions, for the preparation of medicaments, excluding the nitrate salts of Erythromycin, Isoniazid, Pyrazinamide, Metronidazole, Acyclovir.
In the present invention can be used also the nitrate salts of the corresponding nitrooxy derivatives of the above listed antimicrobic agents, said nitrooxy derivatives characterized in that in their molecules there are one or more, preferably one, substituents having the general formula (I-N)
xe2x80x94Bxe2x80x94(W)pxe2x80x94ONO2xe2x80x83xe2x80x83(I-N) 
wherein:
p is 1 or 0;
B=xe2x80x94TBxe2x80x94Yxe2x80x94BIxe2x80x94 wherein TB e TBI are same or different;
TB is a chemical function covalently linked to the chemical or reactive function of the drug molecule and is (CO) or X, wherein X=O, S, NH, with the condition that X=(CO) when the reacting function of the drug is OH or NH2 or SH; TB is X when the reacting function of the drug is a carboxyl group;
TBI=(CO)tx or (X)txx, wherein tx and tax are 0 or 1; with the condition that tx=1 when txx=0, tx=0 when txx=1; X is as above defined;
Y is a bivalent linking bridge chosen between the following structures: 
wherein:
nIX is an integer comprised between 0 and 3, preferably is 1;
nIIX is an integer comprised between 0 and 3, preferably is 1;
RTIX, RTIXxe2x80x2, RTIIX, RTIIXxe2x80x2, same or different each from the other, are H or linear or branched C1-C4 alkyl;
preferably RTIX, RTIXxe2x80x2, RTIIXxe2x80x2, are H.
Y3 is a ring containing at least one salifiable nitrogen atom; preferably Y is an heterocyclic ring containing one or two nitrogen atoms, the ring saturated, unsaturated or aromatic, having preferably 5 or 6 atoms.
An alkylene group Rxe2x80x2 wherein Rxe2x80x2 is a linear or branched C1-C20 alkyl, preferably a C2-C6 alkyl, optionally substituted with one or more of the following groups: xe2x80x94NHCOR3Y, wherein R3Y is a linear or branched C1-C5 alkyl, xe2x80x94NH2, xe2x80x94OH;
A cycloalkylene ring C5-C7, optionally substituted with Rxe2x80x2, being Rxe2x80x2 as above defined, wherein one or more C atoms of the cycloalkylene can be optionally substituted with heteroatoms; 
xe2x80x83wherein n3 is an integer from 0 to 3 and n3xe2x80x2 is an integer from 1 to 3; 
xe2x80x83wherein n3 and n3xe2x80x2 have the meanings above indicated; 
xe2x80x83wherein:
R4Y is OH, H, alcoxy R5YOxe2x80x94 wherein R5Y is a linear or branched or cyclo C1-C10 alkyl, preferably R5Y is methyl;
R2Y is a linear or branched alkenylene C2-C10 containing one or more double bonds, preferably R2Y is an ethenylene group (xe2x80x94CHxe2x95x90CHxe2x80x94); 
wherein R1f=H, CH3 and nf is an integer from 0 to 6;
preferably from 0 to 4;
W of formula (I-N) is the bivalent radical xe2x80x94Tcxe2x80x94YT-wherein:
Tc=(CO) when tx=0, Tc=X when txx=0;
with the proviso that in formula (I-N) when p=1 YT is different from Y and in the bivalent radical B:
Y is Rxe2x80x2 as above defined having a substituent NHCOR3Y, preferably Rxe2x80x2 is a C2 saturated alkyl and R3Y is CH3; Ta=S; TB1 is xe2x80x94COxe2x80x94; preferably Y is xe2x80x94CH2xe2x80x94CH(NHCOCH3)xe2x80x94 and B in formula (I-N) preferably has the following structure: 
xe2x80x83or
Y is a bivalent radical of formula (V-Y), wherein R4Y is OR5Y and R5Y is preferably CH3, R2Y is the group xe2x80x94CHxe2x95x90CHxe2x80x94; preferably Y has the following formula 
Preferably Y3 in formula (II-Y) is selected from the following bivalent radicals: 
Preferably Y3 is a 6-membered aromatic ring containing one nitrogen atom, said ring having the two free valences in the following positions: 2,6; 2,3; 2,5.
The preferred of Y3 is Y12 (pirydil) substituted at positions 2 and 6.
Y1 (pyrazole) can be 3,5-disubstituted.
A further object of the present invention are the nitrate salts of the nitrooxy derivatives of the antimicrobial above listed compounds, preferably having antiviral, antifungal and antibacterial activity, or their pharmaceutical compositions, for the preparation of medicaments, excluding the nitrate salts of the nitrooxy derivatives of Erythromycin, Isoniazid, Pyrazinamide, Metronidazole, Acyclovir when in formula (I-N) p=0.
The derivatives of antibacterial agents having in their molecules one or more of the substituencs of formula (I-N) can be prepared according to methods known in the art.
In general, if in the molecule of the drug, or in the bivalent radicals B or W of formula (I-N) there are more than one reactive groups COOH and/or Hx, X being as above defined, said reactive groups must be protected before the reaction according to the methods known in the art; for example as described in the volume by Th. W. Greene: xe2x80x9cProtective groups in organic synthesisxe2x80x9d, Harward University Press, 1980.
Acyl halides are prepared according to the methods known in the prior art, for example by thionyl or oxalyl chloride, PIII or PV halides in inert solvents under the reaction conditions, such as for example toluene, chloroform, DMF, etc.
1) When the reactive chemical function of the drug is a carboxyl group and p=0 in formula (I-N), the corresponding nitrooxy derivatives can be prepared by the following methods:
1.a) The acid RCOOH (wherein R is the drug radical) and an halogen alcohol derivative of formula HOxe2x80x94Yxe2x80x94Hal, wherein Y is as above defined and Hal is an halogen atom, for example Cl, Br, Iodine, may be coupled to produce the ester of formula (1/C) by treatment with a de-hydrating agent such as N,Nxe2x80x2-carbonyldiimidazol (CDI), N-hydroxy-benzotriazol, and dicyclohexylcarbodiimide (DCC) in the presence of a condensation catalyst such as 4-dimethylaminopyridine (DMAP), in a solvent such as for example DMF, THF, chloroform etc. at a temperature in the range from xe2x88x925xc2x0 C. to 50xc2x0 C. 
1.b) Alternatively the acid RCOOH may first be converted into an alkali metal salt such as sodium or potassium salt and reacted with a dihalogenated derivative of general formula Y(Hal)2, wherein Y and Hal are as above defined.
Rxe2x80x94COONa+Halxe2x80x94Yxe2x80x94Hal-------- greater than Rxe2x80x94COxe2x80x94Oxe2x80x94Yxe2x80x94Halxe2x80x83xe2x80x83(1/B) 
1.c) Alternatively the acid may first be converted to the acyl chloride of formula Rxe2x80x94COxe2x80x94Cl (wherein R is the drug radical) and then is reacted with an halogena alcohol of formula HOxe2x80x94Yxe2x80x94Hal or a dial of formula HOxe2x80x94Yxe2x80x94OH, wherein y is as above defined and Hal is halogen (Cl, Br, I):
Rxe2x80x94COCl+HOxe2x80x94Yxe2x80x94Hal-------- greater than Rxe2x80x94COxe2x80x94Oxe2x80x94Yxe2x80x94Halxe2x80x83xe2x80x83(1/A) 
Rxe2x80x94COCl+HOxe2x80x94Yxe2x80x94HO-------- greater than Rxe2x80x94COxe2x80x94Cxe2x80x94Yxe2x80x94OHxe2x80x83xe2x80x83(1/Axe2x80x2) 
1.d) The acid RCOOH and a dihalogenide compound of formula Halxe2x80x94Yxe2x80x94Hal, wherein Y and Hal are as above defined, may be coupled to form an ester in the presence of a base, in an organic solvent inert in the reaction conditions according to the following scheme:
RCOHal+Halxe2x80x94Yxe2x80x94Hal---xe2x86x92Rxe2x80x94COOxe2x80x94Yxe2x80x94Halxe2x80x83xe2x80x83(1/D) 
1.e) When the compounds obtained in the herein above described reactions have formula Rxe2x80x94COOxe2x80x94Yxe2x80x94Hal, the corresponding nitrooxyderivatives are obtained by reacting the compound Rxe2x80x94COxe2x80x94Oxe2x80x94Yxe2x80x94Hal with AgNO3 in an organic solvent such as acetonitrile, tetrahydrofuran according to the following scheme:
Rxe2x80x94COOxe2x80x94Yxe2x80x94Hal+AgNO3-------xe2x86x92Rxe2x80x94COOxe2x80x94Yxe2x80x94ONO2 
1.f) When the compounds obtained in the herein above described reactions have the formula Rxe2x80x94COOxe2x80x94Yxe2x80x94OH, the hydroxy group is firstly halogenated, for instance by means of PBr3, PCl5, SOCl2, PPh3+I2, then reacted with AgNO3 in an organic solvent such as acetonitrile, tetrahydrofuran.
2) When in formula (I-N) p=0, and the free valence of R is saturated with an hydroxy group, the methods of synthesis of the corresponding nitrooxy derivatives are the following:
2.a) The drug of formula Rxe2x80x94OH and an halogenoacid of formula Halxe2x80x94Yxe2x80x94COOH or an hydroxyacid of formula HOxe2x80x94Yxe2x80x94COOH, wherein Y and Hal are as above defined, may be coupled according to the reactions known in the art to produce the esters of formula (2/A) or (2/B), according to the following schemes:
Rxe2x80x94OHxe2x80x94Halxe2x80x94Yxe2x80x94COCl-----xe2x86x92Rxe2x80x94OCOxe2x80x94Yxe2x80x94Halxe2x80x83xe2x80x83(2/A) 
Rxe2x80x94OHxe2x80x94Halxe2x80x94Yxe2x80x94COCl-----xe2x86x92Rxe2x80x94OCOxe2x80x94Yxe2x80x94OHxe2x80x83xe2x80x83(2/B) 
2.b) When the compounds obtained in the herein above described reactions have the formula Rxe2x80x94OCOxe2x80x94Yxe2x80x94Hal or Rxe2x80x94OCOxe2x80x94Yxe2x80x94OH, the corrresponding nitrooxy derivatives are obtained as described in 1.f and 1.e respectively.
3. When in formula (I-N) p=1 and the reactive group of the drug molecule is a carboxyl group, the methods of synthesis for obtaining the corresponding nitrooxy derivatives are the following ones:
3.a) The drug of formula RCOOH may first be converted to the acyl chloride of formula Rxe2x80x94COxe2x80x94CL (wherein R is the drug radical) and then is reacted with a compound of formula HXxe2x80x94Yxe2x80x94COOH according to the methods known in the art, to obtain a compound of formula Rxe2x80x94COxe2x80x94Xxe2x80x94Yxe2x80x94COOH, that it is converted into the corresponding sodium salt and then reacted with a compound of formula Halxe2x80x94YTxe2x80x94RY wherein Hal e YT are as above defined and RBY is Cl, Br, Iodine, OH:
Rxe2x80x94COHal+HXxe2x80x94Yxe2x80x94COOH---xe2x86x92Rxe2x80x94COxe2x80x94Xxe2x80x94Yxe2x80x94COOHxe2x80x83xe2x80x83(3.A) 
Rxe2x80x94COxe2x80x94Xxe2x80x94Yxe2x80x94COONa+Halxe2x80x94YTxe2x80x94R8---xe2x86x92Rxe2x80x94COxe2x80x94Xxe2x80x94Yxe2x80x94COxe2x80x94YTxe2x80x94R8xe2x80x83xe2x80x83(3.Axe2x80x2) 
xe2x80x83When R8Y=OH, the compound of formula (3.Axe2x80x2) is halogenated as above described in 1.f); when R8Y=Hal the compound of formula (3.Axe2x80x2) is reacted with AgNO3 in an organic solvent such as acetonitrile, tetrahydrofuran:
3.b) When YT is a linear alkylene C4, the acid compound of formula (3.A) is reacted with triphenylphosphine in the presence of an halogenating agent such as CBr4 or N-bromosuccinimide in tetrahydrofuran to give directly the compound of formula (3.Axe2x80x2) wherein RBY=Br, said compound is then converted into the corresponding nitrooxy derivative as described under i.e.
4) When in formula (I-N) p=1 and the reactive group of the antibacterian drug is an hydroxy group, the methods of synthesis for obtaining the corresponding nitrooxy derivatives are the following ones:
4.a) The drug of formula Rxe2x80x94OH and an acyl halogenide of formula HXxe2x80x94Yxe2x80x94COHal wherein Y, X and Hal are as above defined, may be coupled according to the methods known in the art to produce the ester of formula of formula Rxe2x80x94Oxe2x80x94COxe2x80x94Yxe2x80x94XH (4/A), that is then reacted with a compound of formula R8Yxe2x80x94YTxe2x80x94COHal wherein R8Y and YT are as above defined.
Rxe2x80x94OH+HXxe2x80x94Yxe2x80x94COCl---xe2x86x92Rxe2x80x94Oxe2x80x94COxe2x80x94Yxe2x80x94XHxe2x80x83xe2x80x83(4/A) 
Rxe2x80x94Oxe2x80x94COxe2x80x94Yxe2x80x94XH+R8xe2x80x94YTYCOxe2x80x94Hal--xe2x86x92Rxe2x80x94Oxe2x80x94COxe2x80x94Yxe2x80x94Xxe2x80x94COxe2x80x94YTxe2x80x94R8Yxe2x80x83xe2x80x83(4Axe2x80x2) 
4.b) Alternatively, the drug Rxe2x80x94OH is reacted with a compound of formula HXxe2x80x94Yxe2x80x94COOH, wherein X and Y are as above defined, in the presence of dicyclohexylcarbodiimide as described under 1.a, to obtain a compound of formula Rxe2x80x94Oxe2x80x94COxe2x80x94Yxe2x80x94XH, that is then reacted with a compound of formula R8Yxe2x80x94YTxe2x80x94COCl wherein R8Y and YT are as above defined, to give the following compound: Rxe2x80x94Oxe2x80x94COxe2x80x94Yxe2x80x94Xxe2x80x94COxe2x80x94YTxe2x80x94R8Y (4/B) When R8Y=OH the compound corresponding to the formula (4/B) or (4axe2x80x2) is halogenated as above described under 1.f); when R8=Hal the compound of formula (4/B) is reacted with AgNO3 in an organic solvent such as acetonitrile, tetrahydrofuran.
The nitrooxy derivatives of the antibacterian agent can also by prepared according to the synthetic methods described in WO 95/30641 herein incorporated by reference.
In the salts or their compositions according to the present invention also one or more isomers, including optical isomers, when possible, of the above described antimicrobial compounds can be used.
The nitrate salts according to the present invention contain at least one nitrate ion mole/compound mole. Preferably the ratio nitrate ion moles/precursor moles is unitary. Salts having a higher molar ratio are obtained when in the molecule more aminic groups, sufficiently basic to be able to be salified, are present.
The salts of the present invention are formulated in the corresponding pharmaceutical compositions according to well known techniques in the prior art, together with the usual excipients; see for example the volume xe2x80x9cRemington""s Pharmaceutical Sciences 15a Ed.xe2x80x9d
The precursors of the salts belonging to the above mentioned classes are prepared according to the methods described in the Merck Index 14a Ed., herein incorporated by reference.
The nitrate salts of the antibacterial compounds are prepared by the following methods.
When the compound to be salified is available as free base soluble in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is prepared by dissolving the compound in the solvent at a concentration preferably equal to or higher than 10% w/v, adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound. The nitric acid is preferably diluted in the same solvent. Preferably during and after the addition it is cooled at temperatures in the range 0xc2x0 C.-20xc2x0 C.
The product is generally recovered by filtration and washed with the solvent.
When the compound is not very soluble, or it is available under the form of a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents can be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. The precipitation of the nitrate salt can be accelerated by diluting then the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
When the starting compound is salified with hydrochloric acid, it is possible to prepare the nitrate salt by directly adding silver nitrate to the compound solution. After having filtered the silver chloride, the solution is concentrated and cooled for recovering the nitrate salt.
When the starting compound is a salt, the corresponding base can also be released by treatment with a saturated solution of sodium or potassium bicarbonate or carbonate, or with a diluted solution of sodium or potassium hydroxide. The base is then extracted with a suitable organic solvent (for example halogenated solvents, esters, ethers), which is then dried. The organic solution is evaporated and one proceeds according to the previous preparation methods, by dissolving the base in acetonitrile or in the other above mentioned solvents.
The compounds and compositions of the present invention can be used for systemic applications, for example they can be administered by os with formulations known in the prior art such as for example tablets or capsules, or by parenteral route, such as for example by intravenous or intramuscular administration in formulations in sterile apyrogenic physiological solution, optionally additioned with other excipients known in the prior art.
It is possible to use the nitrate salts of the present invention for topical applications, under the form of gels or creams, or by aerosol (by inhalation).
As said, the compounds of the invention are used in the therapy of the same pathologies for which the precursor antimicrobial agents ar used. However since the products of the invention show an improved activity, they can be used even at lower doses. This is advantageous since it allows to avoid the side effects mentioned above for precursors.
The following Examples are given with the only purpose to illustrate the invention and they are not limitative of the same.